This ongoing Program Project Grant was originally initiated in 1985 in order to develop a team approach to clarifying the mechanisms by which common malignancies such as breast, prostate and myeloma affect the skeleton and cause disastrous clinical consequences such as hypercalcemia, bone pain and susceptibility to fracture. This area of research has changed somewhat since the time of the original application 9 years ago. Now, many of the tumor-associated factors with the potential to affect bone cell function have been identified, and the emphasis has changed so that a major objective now is to understand how these factors interact to cause the characteristic bone abnormalities (particularly osteolytic and osteoblastic lesions) seen in different types of malignancy. We have assembled a team of Investigators with skills in bone cell biology, molecular biology, protein chemistry and bone histomorphometry to use state-of-the-art techniques for examining the mechanisms by which bone cell function is altered in a number of in vivo models of human tumors. In the 7 years our group has had support from this grant, we have presented 110 abstracts and published over 200 manuscripts in the general area supported by this grant, and 84 peer- reviewed publications which can be directly ascribed to it. During the next grant period, we wish to emphasize the following modifications in our experimental approaches. 1) reliance in each project on well- described animal models of bone disease which occur in different common human malignancies; 2) extensive use of the powerful morphologic technique of quantitative bone histomorphometry in these in vivo models; and 3) examination of the role of bone itself in promoting growth of those tumors which have a special predilection for bone sites such as breast and prostate cancer and myeloma. We have gathered a team of investigators who have now worked effectively and productively together for a number of years. Our hope is that we will gain insights into mechanisms by which tumor cells affect bone cell function and develop novel approaches at preventing these effects or reversing them once they have become established. These models should enable us to gain information on this common complication of many cancers which is not possible to gather in patients with terminal malignancy.